Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model
| العنوان: | Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model |
|---|---|
| المؤلفون: | Darrell Panza, Kristine Svenson, Jason Shaoyun Xiang, Xianbin Tian, Christian E. Johnson, Xin Xu, James Tobin, Xiangping Li, Huan-Qiu Li, Mylene Perreault, Joel Bard, Tarek S. Mansour, Seung Hahm, Eddine Saiah, Ariful Qadri, Vipin Suri, Eva Chenail, Zhao-Kui Wan, Manus Ipek, Yuzhe Xing |
| المصدر: | Journal of Medicinal Chemistry. 52:5449-5461 |
| بيانات النشر: | American Chemical Society (ACS), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Male, Models, Molecular, medicine.medical_specialty, medicine.medical_treatment, Molecular Conformation, CHO Cells, Crystallography, X-Ray, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, Cricetulus, Pharmacokinetics, In vivo, Cricetinae, Diabetes mellitus, Internal medicine, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Drug Discovery, medicine, Animals, Humans, Obesity, Enzyme Inhibitors, Hydrocortisone, biology, Chemistry, Insulin, medicine.disease, Diet, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine, Cortisone, hormones, hormone substitutes, and hormone antagonists, Ex vivo, medicine.drug |
| الوصف: | Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::42f85d0e0f8af0cfd247553b12a776ed https://doi.org/10.1021/jm900639u |
| رقم الأكسشن: | edsair.doi.dedup.....42f85d0e0f8af0cfd247553b12a776ed |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
|---|